The pharmacokinetics and biochemical efficacy of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) were evaluated in healthy male volunteers after single and multiple oral administration. The mean times to reach peak plasma concentrations (Tmax) of (I) at doses of 5, 10, 20, 50 and 100 mg ranged from 1.8 to 2.8 h, and the corresponding mean peak plasma concentrations (Cmax) were 38.1, 81.5, 147.1, 442.0 and 835.5 ng/ml, respectively. The drug disappeared from the systemic circulation with half-lives (t1/2) of 4.7-7.1 h. The mean values of the area under the curve (AUC0-24) and Cmax increased linearly in a dose-dependent manner. After multiple oral administration of (I) (10 mg/d) for 7 days, Cmax and AUC increased slightly during administration, however, there were no significant differences between day 4 and day 7. Although there were large intersubject differences in the 24 h plasma levels after each dosing, no accumulation of (I) occurred after 7 days dosing. Serum 5-alpha-dihydrotestosterone (DHT) was markedly reduced at all dose levels. The mean serum levels of DHT at 24 h post-dosing decreased to 27-42% of that before dosing. On the other hand, the serum testosterone (T) did not change significantly. After multiple administration of (I), serum DHT was significantly reduced and remained suppressed for up to 7 days after the final dosing.

5-alpha Reductase Inhibitors↗

PubMedDate not supplied

Combined medical and surgical treatment of severe vernal keratoconjunctivitis.

PURPOSE: We report the efficacy of an alternative method of treatment for vernal keratoconjunctivitis (VKC) that consists of excision of the palpebral conjunctiva followed by supratarsal injection of corticosteroid and five times daily topical application of 0.05% cyclosporine A (CsA) and cromolyn sodium. METHODS: We evaluated 10 patients with severe treat-resistant VKC with corneal complications. The patients were evaluated for symptoms and for signs, including conjunctival changes, corneal limbal infiltrates, vascularization, reduction of epitheliopathy, meibomitis, visual acuity, intraocular pressure, and pathologic evaluation, before and after treatment. RESULTS: All patients showed marked improvement after 2 weeks of treatment. The symptoms (P <.01), signs (P <.02), and the visual acuity of all patients (P <.01) had significantly improved following treatment. Histological examination showed significant inflammatory cell decreases 4 weeks after surgery (P <. 05). CONCLUSION: Surgery plus topical drug therapy may be useful in treating patients with very severe VKC.

Adolescent↗

PubMedDate not supplied

Acquired expression of hst-1 in an autonomous subline (Chiba subline 2) derived from androgen-responsive mouse mammary tumor (Shionogi carcinoma 115).

Since growth of Shionogi Carcinoma 115 (SC 115) and its autonomous subline (CS 2) were regulated by fibroblast growth factor-like peptide, expression of int-2 and hst-1 was examined in these cell lines. Hybridization of genomic DNA with long terminal repeat of mouse mammary tumor virus (MMTV) revealed the same pattern of restriction fragments, showing the same integration of MMTV. Although weak expression of int-2 was noticed in the two cells, clear expression of hst-1 was seen only in CS 2 cultured with/without testosterone. It is suggested that autonomous growth of androgen-unresponsive CS 2 is connected with expression of hst-1.

Animals↗

PubMedDate not supplied

A case of an infertile man with short-tailed spermatozoa.

Ejaculated spermatozoa from an infertile patient were examined by scanning and transmission electron microscopy. All spermatozoa had abnormalities in the tail region. The abnormalities were divided into three types: (a) spermatozoa with a spherical tail. The tail was larger than the head in volume. This type of abnormality accounted for about 60% of the population; (b) spermatozoa with a blunt tail. The tails were about 2 microns in diameter and about 7 microns in length. This type of abnormality accounted for about 30% of the population of an ejaculate; (c) spermatozoa without a tail. Some of these had only a rudimentary tail. About 10% of the population belonged to this type. In types A and B, all components of the tail, except for dynein arms, were observed, but they were severely disarranged. Biopsy specimens of the testes and of the nasal mucosa of this patient were also investigated. The testicular biopsy showed defects in manchette formation. Normal development of the manchette could not be observed. The nasal epithelium showed absence of the inner dynein arms in the cilia.

Adult↗

PubMedDate not supplied

Mutational state of von Hippel-Lindau and adenomatous polyposis coli genes in renal tumors.

Genetic alterations of the von Hippel-Lindau (VHL) tumor suppressor gene and the adenomatous polyposis coli (APC) gene in renal tumors were examined by PCR-SSCP analysis and direct sequencing. Tissues from 58 primary sporadic human renal cell tumors (49 clear-cell carcinomas, 6 non-clear-cell carcinomas and 3 oncocytomas) from Japanese patients were used in this study. Somatic VHL mutations were detected in 26 (53%) of the clear-cell carcinomas, although no mutations in this gene were observed in any non-clear-cell carcinomas or oncocytomas. The frequency of mutations did not correlate with histological grade, clinical stage or any of several other clinical factors examined. No differences in the frequency of VHL mutations or in the exons where mutations occurred within the gene were evident when we compared our results with those reported for American patients. However, frameshifts were more common in our Japanese panel of tumors than in American cases, where single-point mutations appear to be more frequent. No APC gene mutation was detected in any of our samples. These results indicate that VHL gene mutations are related to the carcinogenesis of the clear-cell type of primary renal cell carcinomas, whereas alteration of the APC gene is not involved in the pathogenesis of this cancer.

Adenomatous Polyposis Coli↗

PubMedDate not supplied

Apoptosis in androgen-independent mouse mammary tumor cells induced by 5-fluorodeoxyuridine but not by androgen withdrawal.

Androgen-dependent tumors eventually progress to independent tumors after androgen withdrawal. Androgen-dependent SC 115 cells could not grow in serum free culture without testosterone. Androgen-independent CS 2 cells, however, could grow whether androgen was present in the media or not. Based upon the temporal sequence of DNA fragmentation, morphological changes and loss of cell viability, androgen withdrawal did not induce the programmed cell death (apoptosis) of CS 2 cells in serum free culture. However, CS 2 cells as well as SC 115 cells retained the ability to undergo apoptosis with 5-fluorodeoxyuridine (FUdR) treatment. Northern blot analysis was used to identify a series of genes and whether the expressions of these per cell changed during apoptotic pathway (i.e. testosterone repressed prostatic message-2; TRPM-2, transforming growth factor-beta 1; TGF-beta 1, glucose regulated 78 kilodalton protein; GRP-78). Although the expression of these genes was increased in SC 115 cells after androgen depletion, none of the genes were induced by androgen withdrawal in CS 2 cells. During the apoptotic process induced by FUdR, mRNA expression of these genes was increased in CS 2 cells as well as in SC 115 cells. These results demonstrate that androgen-independent CS 2 cells do not undergo apoptosis induced by androgen withdrawal, but retain the ability to undergo apoptosis by FUdR. The apoptotic pathway is same whether the cells are androgen-dependent or independent.

Animals↗